Use of extracts of ginkgo biloba for preparing a medicament

ABSTRACT

The invention relates to the use of  Ginkgo biloba  extracts for preparing a medicament intended to ease the withdrawal of individuals dependent on the consumption of a substance engendering dependency and/or addiction, such as in particular alcohol, amphetamines, tobacco, drugs inducing toxicomania.

[0001] The invention relates to the use of extracts of Ginkgo biloba forpreparing a medicament intended to ease the withdrawal of individualswho are dependent on the consumption of a substance engenderingdependency and/or addiction, such as in particular alcohol,amphetamines, tobacco, drugs inducing toxicomania.

[0002] It is already known that extracts of Ginkgo biloba have anactivity in the cardiovascular field (in particular the reduction ofplatelet adhesion), in the central nervous field (in particular aneuroprotective activity) or in the neurosensory system (in particularretinal protection); cf. for example DeFeudis et al., Ginkgo bilobaExtract (EGb 761®), Pharmaceutical Activities and Clinical Applications(Elsevier, Paris, 1991). Their preparation has been the subject of acertain number of patents, of which there can be mentioned the EuropeanPatents EP 431 535 and EP 431 536, and the American Patent U.S. Pat. No.5,389,370.

[0003] Now the Applicant has just found that certain extracts of Ginkgobiloba also have useful new pharmacological properties, namely easingthe withdrawal of subjects addicted to alcohol or drugs, and moregenerally of subjects dependent on a substance engendering dependencyand/or addiction. The Applicant observed that the administration ofthese extracts resulted in an attenuation of the withdrawal symptoms.

[0004] A subject of the invention is therefore the use of these extractsfor preparing a medicament intended to ease the withdrawal ofindividuals dependent on the consumption of a substance engenderingdependency and/or addiction, such as in particular alcohol,amphetamines, tobacco, drugs inducing toxicomania.

[0005] By drugs inducing toxicomania is understood in particularmorphine and its derivatives, opium and opiates, cocaine, crack, andmore generally all substances, including any medicamentous substances,on which a subject can become dependent.

[0006] By extract of Ginkgo biloba is understood at least one of theindividual compounds which can be obtained by extraction from the Ginkgobiloba L tree, and in particular a flavonoid compound or a terpene suchas a ginkgolide or a bilobalide, or also a mixture of the latter.Preferably, the extract used will be such that it contains an effectivequantity of ginkgolides. For the uses according to the invention, anextract of type EGb 761 or CP 401 can for example be chosen.

[0007] By ginkgolide is understood all the natural ginkgolides obtainedfrom the Ginkgo biloba tree, as well as synthetic ginkgolides and theirderivatives (resulting for example from an acetylation or alkoxylationreaction) and pharmaceutically active salts. The ginkgolides used canfor example be ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J orginkgolide M (structures given in the diagram below; these compounds canbe isolated from extracts of Ginkgo biloba leaves—see GINKGOLIDES,Chemistry, Biology, Pharmacology and Clinical Perspectives, published byP. Braquet, J. R. Prous Science Publishers, in particular Volumes 1(1988) and 2 (1989)). Glycosylated derivatives of ginkgolides oralkoxylated or acetylated derivatives of ginkgolides can also be used.By alkoxylated derivative of ginkgolide is understood a ginkgolidederivative comprising at least one linear or branched alkoxy group,instead of a hydroxy group (these compounds are described in FrenchPatent Application No. FR 88.14392). Similarly, by acetylated derivativeof ginkgolide is understood a derivative of ginkgolide comprising atleast one acetate group instead of a hydroxy group. Structure ofginkgolides A, B, C, J and M

Ginkgolide W X Y Z A OH OH H H B OH OH OH H C OH OH OH OH J OH OH H OH MH OH OH OH

[0008] By extract of type EGb 761 is understood an extract of acomposition substantially identical to that of the standardized extractEGb 761 as defined in particular in the following article: K. Drieu, Lapresse médicale, 31, 25 September 1986, supplement devoted to theextract of Ginkgo biloba (EGb 761), 1455-1457; or in the EuropeanPatents EP 431 535 and EP 431 536; by extract of type EGb 761 istherefore understood in particular extracts of Ginkgo biloba comprising20 to 30% of flavoneglycosides, 2.5 to 4.5% of ginkgolides A, B, C andJ, 2 to 4% of bilobalide, less than 10% of proanthocyanidines and lessthan 10 ppm, and preferably less than 5 ppm, of compounds of alkylphenoltype, and in particular extracts of Ginkgo biloba comprisingapproximately 24% of flavoneglycosides, 3.1% of ginkgolides A, B, C andJ, 2.9% of bilobalide, 6.5% of proanthocyanidines and less than 1 ppm ofcompounds of alkylphenol type. By extract of type CP 401 is understoodextracts such as those which are presented in the Patent U.S. Pat. No.5,389,370, in particular extracts of Ginkgo biloba containing 5.5 to 8%of ginkgolides A, B, C and J, 40 to 60% of flavoneglycosides and to 7%of bilobalide, and quite particularly extracts containing approximately7% of ginkgolides A, B, C and J, 50% of flavoneglycosides and 6% ofbilobalide.

[0009] According to another aspect of the invention, the extract ofGinkgo biloba used will comprise more than 5% of ginkgolides, and morepreferably more than 50% of ginkgolides.

[0010] The invention also relates to the use of a ginkgolide or one ofits derivatives or pharmaceutically active salts for preparing amedicament intended to ease the withdrawal of individuals dependent onthe consumption of a substance engendering dependency and/or addiction,such as in particular alcohol, amphetamines, tobacco, drugs inducingtoxicomania. Preferably, the ginkgolide used for this aspect of theinvention will be ginkgolide A or ginkgolide B.

[0011] The invention also relates to the use of a compound of generalformula (I)

[0012] in which W, X, Y and Z independently represent the H, OH, linearor branched alkoxy or O-G_(S), G_(S)-OH radicals representing a mono- ordisaccharide, or one of their derivatives or analogues,

[0013] it being understood that at least one of W, X, Y or Z representsan O-G_(S) radical,

[0014] for preparing a medicament intended to ease the withdrawal ofindividuals dependent on the consumption of a substance engenderingdependency and/or addiction, such as in particular alcohol, tobacco,amphetamines, drugs inducing toxicomania.

[0015] The invention preferably relates to the use of a compound ofgeneral formula (I)

[0016] in which X represents an OH or O-G_(S) radical, G_(S)-OHrepresenting a mono- or disaccharide, or one of their derivatives oranalogues, and:

[0017] either W represents an OH or O-G_(S) radical, Y represents H andZ represents H;

[0018] or W represents an OH or O-G_(S) radical, Y represents an OH orO-G_(S) radical and Z represents H;

[0019] or W represents an OH or O-G_(S) radical, Y represents an OH orO-G_(S) radical and Z represents an OH or O-G_(S) radical;

[0020] or W represents an OH or O-G_(S) radical, Y represents H and Zrepresents an OH or O-Gs radical;

[0021] or W represents H, Y represents an OH or O-G_(S) radical and Zrepresents an OH or O-Gs radical;

[0022] or W represents an OH or O-G_(S) radical, Y represents a linearor branched alkoxy radical and Z represents H;

[0023] it being understood that at least one of W, X, Y or Z representsan O-G_(S) radical,

[0024] for preparing a medicament intended to ease the withdrawal ofindividuals dependent on the consumption of a substance engenderingdependency and/or addiction, such as in particular alcohol, tobacco,amphetamines, drugs inducing toxicomania.

[0025] The invention relates quite particularly to the use of a compoundof general formula (I)

[0026] in which X represents an OH or O-G_(S) radical, G_(S)-OHrepresenting a mono- or disaccharide, or one of their derivatives oranalogues, and:

[0027] either W represents an OH or O-G_(S) radical, Y represents H andZ represents H;

[0028] or W represents an OH or O-G_(S) radical, Y represents an OH orO-G_(S) radical and Z represents H;

[0029] or W represents an OH or O-G_(S) radical, Y represents a linearor branched alkoxy radical and Z represents H;

[0030] it being understood that at least one of W, X, Y or Z representsan O-G_(S) radical,

[0031] for preparing a medicament intended to ease the withdrawal ofindividuals dependent on the consumption of a substance engenderingdependency and/or addiction, such as in particular alcohol, tobacco,amphetamines, drugs inducing toxicomania.

[0032] By linear or branched alkoxy radical is understood in the presentdescription an alkoxy radical the linear or branched carbon containingchain of which contains 1 to 6 carbon atoms. By derivative or analogueof mono- or disaccharides is understood compounds such asN-acetylglucosamine, N-acetylalosamine, galactosamine, mannoseamine,N-tosylhydrazone, etc.

[0033] Preferably, O-G_(S) will be chosen such that G_(S)-OH belongs tothe group comprising abequose, rhamnose, arabinose, ribose, xylose,2-deoxy-ribose, glucose, galactose, mannose, 2-deoxyglucose, fructose,fucose, N-acetylglucosamine, N-acetylalosamine, galactosamine,mannosamine, saccharose, lactose, maltose, cellobiose and trehalose.Even more preferentially, O-G_(S) will be chosen such that G_(S)-OHbelongs to the group comprising glucose and lactose.

[0034] The invention therefore also relates to the use of glycosylatedderivatives of ginkgolides, more particularly those of ginkgolides A andB, the glycosyl groups suitable for the invention having been describedpreviously.

[0035] The different processes for obtaining glycosylated derivatives ofginkgolides or alkoxylated ginkgolides (i.e. those resulting from aglycosylation reaction carried out on at least one of the OH groups ofginkgolides or their alkoxylated derivatives) are described in thefollowing publication: Weber, M. and Vasella, A., Helv. Chim. Acta, 80(1997), 2352-2367.

[0036] The pharmaceutical compositions comprising a compound of theinvention can be in the form of solids, for example powders, granules,tablets, gelatin capsules, liposomes or suppositories. Appropriate solidsupports can be, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

[0037] The pharmaceutical compositions containing a compound of theinvention can also be presented in liquid form, for example, solutions,emulsions, suspensions or syrups. Appropriate liquid supports can be,for example, water, organic solvents such as glycerol or glycols, aswell as their mixtures, in varying proportions, in water.

[0038] The administration of a medicament according to the invention canbe carried out by topical, oral, parenteral route, by injection(intramuscular, sub-cutaneous, intravenous, etc.), etc.

[0039] The administration dose envisaged for a medicament according tothe invention is comprised between 0.1 mg and 10 g according to the typeof substance on which the subject to be treated is dependent.

[0040] Unless they are defined differently, all the technical andscientific terms used here have the same meaning as that usuallyunderstood by an ordinary specialist in the field to which thisinvention belongs. Similarly, all publications, patent applications, allpatents and all other references mentioned here are incorporated by wayof reference.

[0041] Pharmacological Study of the Products of the Invention:

[0042] 1. Study of the Effects of Extracts of Ginkgo biloba on AlcoholDependency:

[0043] Two studies were carried out: one relates to the effects of EGb761, the other to the effects of another extract of Ginkgo biloba, CP401, which does not contain bilobalide but twice as much ginkgolides asEGb 761 (6%).

[0044] 1) Rats are treated for 15 days with alcohol (they areadministered 10% ethanol in their drinking water for the first week andthen 12.5% ethanol). They are given 50 or 100 mg/kg of EGb 761 per dayby oral route (gavage) for the 5 days before the absorption of alcoholis stopped (from the 11th day) and the 3 days after it is stopped.

[0045] The behavioural symptoms were evaluated for 3 days after theabsorption of alcohol is stopped in three groups of rats (n=6): thecontrol group having received only alcohol, one group having receivedalcohol and treatment with 50 mg/kg of EGb 761 and another group havingreceived alcohol and treatment with 100 mg/kg of EGb 761, the treatmentswith EGb 761 having been administered under the conditions describedabove. The results of these tests are shown in table (I) which can befound in appendix I.

[0046] In the animals which received EGb 761, it can be observed thatthe withdrawal symptoms (7 criteria) are reduced in a dose-dependentmanner and that the animals also have reduced motor hyperactivity.

[0047] 2) Rats are treated for 15 days with alcohol (they are given 10%ethanol in their drinking water for the first week and then 12.5%ethanol). They are administered 50 mg/kg of CP 401 extract per day byoral route (gavage) for the 5 days before the absorption of alcohol isstopped (from the 11th day) and the 3 days after it is stopped.

[0048] The behavioural symptoms were evaluated for the 3 days after theabsorption of alcohol was stopped in three groups of rats (n=6): thecontrol group only having received alcohol and the other group havingreceived alcohol and treatment with 50 mg/kg of CP 401 extractadministered under the conditions described above. The results of thesetests are shown in table (II) which can be found in appendix I.

[0049] It is observed that the animals which received the CP 401 extractshow a reduction in the symptoms linked with withdrawal compared withthe intoxicated control animals.

[0050] 2. Study of the Effects of Ginkgo biloba Extracts onSensitization to Amphetamine:

[0051] An injection of amphetamine (0.5 mg/kg IP) provokes motorhyperactivity in the rat (measured by actimetry). Administration eighttimes, every other day, of the same dose of amphetamine results in aprogressive increase in locomotive activity: this phenomenon is called“sensitization”.

[0052] For 8 days before the administration of amphetamine andthroughout this administration, rats (n=8) subjected to theadministration of amphetamine as described above were subjected totreatment by oral route with a dose of EGb 761 of 100 mg/kg per day orof a dose of 5 mg/kg per day of ginkgolide A.

[0053] Actimetry measurements were carried out for 1 hour after theadministration of the amphetamine on the 9th (first day on whichamphetamine was administered), 13th, 17th, 21st and 25th day. Theresults of these tests are shown in A which can be found in appendix II.

[0054] It is observed that behavioural sensitization to amphetamine isreduced in the animals which received 5 mg/kg per day of ginkgolide A.An enhanced and quite significant effect is observed with EGb 761 at 100mg/kg per day.

[0055] 3. Study of the Effects of Ginkgo biloba Extract EGb 761 onMorphine Withdrawal Syndrome:

[0056] Rats are treated every 8 hours (3 times per day) for 10 days witha dose of morphine by sub-cutaneous route resulting in motorhyperactivity (measured by actimetry). On the 11th day, they areadministered naloxone (3 mg/kg IP) and the withdrawal signs are observedfor 60 minutes: a series of behavioural signs is quantified, a seriesmeasured (hypothermia, weight loss) or a series graded (scale with 4levels).

[0057] Two groups of 8 rats are treated with EGb 761 (50 or 100 mg/kgper day) for 4 days before the administration of naloxone and 2 hoursbefore it. A group of intoxicated control rats only receives injectionsof morphine before the naloxone and an absolute control group onlyreceives naloxone.

[0058] Statistical analysis of the batches is carried out using thefollowing tests: parametric Anova, Barlett's test to check thehomogeneity of variances and Dunnett's test for multiple comparisons.

[0059] The results quantified by counting for the different behaviouralparameters analyzed are shown in table (III) which can be found inappendix III. TABLE I Influence of treatment with substance EGb 761 onthe number of observations of each symptom of abstinence at 24 hoursafter withdrawal Treatment (mg/kg) TRE SNO CHA TWI MOT ESC JUM none 717  15  12  11  6 5 EGb 761 (50) 5 9 8 6 6 3 2 EGb 761 (100) 0 5 4 2 3 01

[0060] TABLE II Influence of treatment with substance CP 401 on thenumber of observations of each symptom of abstinence at 24 hours afterwithdrawal Treatment (mg/kg) TRE SNO CHA TWI MOT ESC JUM none 6 19 12 15  9 6 6 CP 401 (50) 4 11 6 7 5 4 3

[0061] Legend common to Tables I and II TRE: trembling in body SNO:snorting CHA: chattering of teeth TWI: twitching of ears MOT: motoractivity ESC: attempted escapes JUM: jumps

[0062] The symptoms are graded from 0 to 3 according to their intensity(0=slight; 3=very pronounced).

TABLE III Influence of treatment with substance EGb 761 on the number ofobservations of each of the symptoms of abstinence during morphinewithdrawal Symptoms Group 1 Group 2 Group 3 Jumps 0.0 ± 0.0 1.00 ± 0.330.50 ± 0.19 Stiffening 9.88 ± 1.03 1.13 ± 0.40 5.63 ± 1.00 Snorting 0.25± 0.16 2.75 ± 0.70 0.88 ± 0.29 Jerking of head 0.0 ± 0.0 5.50 ± 1.132.43 ± 0.48 Yawning 0.75 ± 0.41 2.00 ± 0.78 0.88 ± 0.40 Chattering orgrinding of 0.0 ± 0.0 4.75 ± 0.86 1.75 ± 0.45 teeth Burying 0.25 ± 0.161.38 ± 0.46 0.25 ± 0.16 Excessive scratching 0.0 ± 0.0 1.13 ± 0.48 0.38± 0.26 Grooming 6.00 ± 1.39 1.38 ± 0.53 4.25 ± 1.31

1. Use of a Ginkgo biloba extract for preparing a medicament intended toease the withdrawal of individuals dependent on the consumption of asubstance engendering dependency and/or addiction, such as in particularalcohol, amphetamines, tobacco, drugs inducing toxicomania.
 2. Useaccording to claim 1, characterized in that the Ginkgo biloba extract isan extract of type EGb
 761. 3. Use according to claim 1, characterizedin that the Ginkgo biloba extract is an extract of type CP
 401. 4. Useaccording to claim 1, characterized in that the Ginkgo biloba extractcontains at least 5% of ginkgolides.
 5. Use according to claim 4,characterized in that the Ginkgo biloba extract contains at least 50% ofginkgolides.
 6. Use of a compound of general formula (I)

in which w, x, y and z independently represent the H, OH, linear orbranched alkoxy or O-G_(S) radicals, G_(S)-OH representing a mono- or adisaccharide, or one of their derivatives or analogues, it beingunderstood that at least one of W, X, Y or Z represents an O-G_(S)radical, for preparing a medicament intended to ease the withdrawal ofindividuals dependent on the consumption of a substance engenderingdependency and/or addiction, such as in particular alcohol,amphetamines, tobacco, drugs inducing toxicomania.
 7. Use according toclaim 6, characterized in that: either W represents an OH or O-G_(S)radical, Y represents H and Z represents H; or W represents an OH orO-G_(S) radical, Y represents an OH or O-G_(S) radical and Z representsH; or W represents an OH or O-G_(S) radical, Y represents an OH orO-G_(S) radical and Z represents an OH or O-G_(S) radical; or Wrepresents an OH or O-G_(S) radical, Y represents H and Z represents anOH or O-G_(S) radical; or W represents H, Y represents an OH or O-G_(S)radical and Z represents an OH or O-Gs radical; or W represents an OH orO-G_(S) radical, Y represents a linear or branched alkoxy radical and Zrepresents H; it being understood that at least one of W, X, Y or Zrepresents an O-G_(S). radical
 8. Use according to claim 6 or 7,characterized in that: either W represents an OH or O-G_(S) radical, Yrepresents H and Z represents H; or W represents an OH or O-G_(S)radical, Y represents an OH or O-G_(S) radical and Z represents H; or Wrepresents an OH or O-G_(S) radical, Y represents a linear or branchedalkoxy radical and Z represents H; it being understood that at least oneof W, X, Y or Z represents an O-G_(S). radical
 9. Use of a ginkgolide orone of its glycosylated, alkoxylated or acetylated derivatives, or of apharmaceutically active salt of the latter for preparing a medicamentintended to ease the withdrawal of individuals dependent on theconsumption of a substance engendering habituation and/or addiction,such as in particular alcohol, amphetamines, tobacco, drugs inducingtoxicomania.
 10. Use according to claim 9, characterized in that theginkgolide is ginkgolide A or ginkgolide B.